The Parthian Empire was the dominating force on the Iranian plateau beginning in the late 3rd century BCE, and intermittently controlled Mesopotamia between ca 190 BC and AD 224.

The Parthians were an illiterate nomadic people, thought to have spoken an Indo-Iranian languages, who arrived at the Iranian plateau from Central Asia. They were consummate horsemen, known for the 'Parthian shot' turning backwards at full gallop to loose an arrow directly to the rear. Later, at the height of their power, Parthian influences reached as far as Ubar in Arabia, the nexus of the frankincense route, where Parthian-inspired ceramics have been found. The power of the early Parthian empire seems to have been overestimated by some ancient historians, who could not clearly separate the latter, very strong empire from its rather obscure origins.

Initially, a king named Arsaces (possibly of a nomad tribe named Parni, a name whose relation to the word Parthian is much debated, or according to Armenian sources of White Hun origins) made himself independent of Seleucid rule in remote areas of northern Iran ca 250 BC, where his descendants of the same name ruled until Antiochus III the Great briefly made them submit to the Seleucid empire again in 206 BC.

It was not until the second century BC that the Parthians profited from the increasing Seleucid weakness and gradually captured all of their territories east of Syria. Once the Parthians had captured Herat, the movement of trade along the Silk Road to China was effectively choked off, and the post-Alexandrian Hellenistic kingdom in Bactria was doomed. It fell to the Seleucid monarchs to hold the line against the Parthians. Antiochus IV Epiphanes spent his last years fruitlessly battling the Parthians in the endless war, until he died in 161 BCE. The Parthians were able to take advantage of Seleucid weakness during the dynastic squabbles that followed Antiochus' death. In 141 BCE, the Parthian king Mithradates I captured the Seleucid monarch, Demetrius Nicator, and held him captive for ten years, while the Parthians overwhelmed Mesopotamia and Media.

By 129 BCE the Parthians were in control of all the lands right to the Tigris River, and established their winter encampment at Ctesiphon on the banks of the Tigris downstream from modern Baghdad. Ctesiphon was a small suburb directly across the river from Seleucia, the most populous Hellenistic city of western Asia. Seleucia they only harassed; they needed its wealth and trade, and the city preserved its independence and Greek culture. In the heat of the Mesopotamian summer, the Parthian horde would withdraw to the ancient Persian capitals of Susa and Ecbatana (modern Hamadan).

In the first century BCE, the Parthians intervened frequently in eastern Mediterranean politics from their capital at Ctesiphon. They clashed with the Romans, gaining respect when they managed to defeat the army of Crassus (53 BCE). Having established themselves across most of the old Persian empire, the Parthians became arch-enemies of Rome, whose Eastern campaigns (for instance under Trajan and Septimius Severus) never crushed the resilient and somewhat de-centralized Parthian 'empire,' but bled capital from Rome.

In AD 224, Ardashir, governor in the Achaemenid home province of Fars/Persis, overthrew Artabanus V and established the Sassanid dynasty.

Little is known of the Parthians: they had no literature of their own and consequently their written history consists of biased descriptions of conflicts with Romans, Greeks, Jews and — at the far end of the Silk Road — the Chinese empire. Their strength was a combination of the guerilla warfare of a mounted nomadic tribe with sufficient organisation to build a vast empire, even if it never matched the two Persian empires in strength. Vassal kingdoms seem to have made up a large part of their territory (see Tigranes I of Armenia, and Hellenistic cities enjoyed a certain autonomy. After their defeat the Parthians, at this point no doubt a thin stratum of nobles, seem to have vanished with few traces.